Evolution-proof malaria control

In treating malaria it is crucial to understand evolutionary dynamics. The problem with insecticides such as DDT is that it kills mosquitos (Anopheles) almost immediately after contact, and thus imposes very strong selection for resistance against the insecticide. The mosquitos evolve resistance within a few years, rendering the whole population immune and the insecticide worthless.

It is also important to understand that while mosquitos is the target for the insecticides, they are really just the carrier of the malaria parasites, Plasmodium falciparum. Consequently, it would be beneficial if there was some way to fight the parasite while not causing the mosquito populations to evolve resistance. And there is indeed a way that could be done, because of the fact that the parasite takes some time to develop within the mosquito. Consider these observations:

The gonotrophic cycle (female mosquitos feed, convert a blood meal into eggs*, lay the eggs, and then seek out a new blood meal) is two to four days long.

Natural mortality (without insecticides) is so high that few females go through more than a few gonotrophic cycles before they die.

Development of the parasite is rather slow. It takes about ten to sixteen days (two to six gonotrophic cycles) for it to develop and move to the salivary glands of the host, where it can be transmitted to humans.

The obvious conclusion is that killing only old mosquitos would solve the problem of the parasite infecting humans, and would avoid selection for mosquito resistance against insecticides. This is exactly what Read et al. propose. They suggest a number of approaches through which only older mosquitos would suffer, and then present a numerical model that shows how such control would play out:

Low sublethal doses of insecticides accumulating after continued exposure could result in death of older mosquitos.

In other words, it might even be the case that simply lowering the concentration of insecticides would be sufficient to eradicate malaria. Fancy that!

That would be an enormous benefit. There are between 350 and 500 million cases of malaria every year, and a resulting one to three million deaths, of which the majority is African children. It would totally rock.

Unfortunately, nothing much in science is as straightforward as that. The majority of the work done by Read et al. was numerical. Their model aimed to quantify to what extent the use of insecticides acting at later gonotrophic cycles can prevent the evolution of resistance. Figure A below shows the fraction of resistant mosquitos as a function of time for con(ventional) insecticides and different hypothetical late-life-acting (LLA) insecticides that kill mosquitos from their second through sixth gonotrophic cycles. The paper does not specify the time-units on the x-axis, so we cannot tell when the mosquitos evolve resistance. But if we assume that it takes one to two years for them to evolve resistance to conventional insecticides, it looks like it takes approximately five times longer in the case of C3, which is five to ten years. Quite an improvement, but not exactly evolution-proof.

The numbers in the second column in B, the relative fitness of mosquitos in the presence of insecticide, needs to be below 1 for the insecticide to be evolution-proof. If there was a way to lower it, it would theoretically be possible to use the same insecticide forever, and never need to develop new ones, as is the case today.

In figure 3 we see that the relative fitness of the infected mosquitos can indeed drop below 1 (the green columns). This happens when there is an additional cost on the mosquitos of being infected with the parasite, which kills an extra fraction of mosquitos every day. Further, if the insecticide affects uninfected mosquitos less than infected ones, then it also gets easier to lower the relative fitness of infected mosquitos.

Read et al. concludes by scaring us with the prospect of disaster if the evolution of resistance is ignored:

The Global Malaria Action Plan (GMAP) [10] has laudable ambitions of spraying 172 million houses annually, and distributing 730 million insecticide-impregnated bed nets by the year 2010. If implemented with existing insecticides, this program will impose unprecedented selection for resistance. The historical record [22], and theory (e.g., Figure 1) shows that the medium-term prognosis for the insecticides currently in use is inescapably poor. Transitioning to an LLA insecticide strategy could see the benefits of the massive GMAP effort sustained, and could maintain for the long term the contribution of several key vector control tools to the goal of eradication. Failure to address evolution now runs the risk of replaying history [22]: operational disaster and a derailing of the whole malaria control agenda.

5 comments:

I like the idea of the paper, and killing old mosquitoes is probably a good idea, but wouldn't that just select for more rapidly developing parasites?

Perhaps more rapid development is difficult to achieve, but I wouldn't put it past those tricky little buggers. Especially if we made it really really fitness enhancing for them to develop more quickly.

I like the idea of the paper, and killing old mosquitoes is probably a good idea, but wouldn't that just select for more rapidly developing parasites? Aprasad, this is a very important caveat, and one that I simply forgot to mention in the post.

The authors themselves comment on it:

The late-life killing insecticides we are proposing here work because of the time Plasmodium takes to develop in mosquitoes. Could these insecticides select more rapidly developing parasites [82,88]? They might, but the short lives of mosquitoes must already be imposing intense natural selection for shorter extrinsic incubation periods, a selection pressure that must be further exacerbated by conventional insecticides. The apparent lack of response to this selection implies that significant fitness gains result from prolonged development [46,89], gains which presumably accrue through increased infectiousness [74]. It might be that LLA insecticides would add sufficient additional selection to offset these, but if it did, the resulting evolution would presumably generate substantially less-fit malaria parasites. Further investigation of this possibility is certainly warranted; in the meantime we note that the hypothetical evolution of significantly less-infectious parasites must be of less public health significance than the observed failure of existing insecticides in the face of resistance evolution.In other words, the possibility for the parasites evolving is there, but they are perhaps already pressed to develop as fast as possible, and futher gains are unlikely.

Pleiotropy comes from the Greek πλείων pleion, meaning "more", and τρέπειν trepein, meaning "to turn, to convert". It designates the occurrence of a single gene affecting multiple traits, and is a hugely important concept in evolutionary biology.

I'm a postdoc at UC Santa Barbara.

All Many aspects of evolution interest me, but my research focus is currently on microbial evolution, adaptive radiation, speciation, fitness landscapes, epistasis, and the influence of genetic architecture on adaptation and speciation.